Solid Oral Sulfate Salt Formulations For Cleaning A Colon And Methods of Using Same

ABSTRACT

Disclosed herein are solid oral dosage formulations comprising sodium sulfate, magnesium sulfate, and potassium chloride for inducing purgation of the colon of a subject. Furthermore, the disclosed compositions and formulations are useful to cleanse the colon when administered in sufficient quantities. Methods for inducing purgation of the colon and for cleansing the colon are also disclosed.

FIELD

This disclosure relates generally to the field of medicine andparticularly to gastrointestinal diagnostic and surgical procedures.

BACKGROUND

When performing medical or diagnostic procedures on the colon, the colonmust be cleansed of fecal matter to permit adequate visualization of theintestinal mucosa. This is important prior to, for example, diagnosticprocedures such as flexible sigmoidoscopy or colonoscopy, diagnosticexaminations widely performed to screen patients for diseases of thecolon. In addition, it is important that the intestines be cleansedthoroughly in order to obtain satisfactory radiographs of the colon.

Existing bowel preparations are generally presented in a liquid form,such as the isotonic large volume preparations GoLYTELY and NuLYTELYwhich are based on polyethylene glycol (PEG) as the osmotic agent, orthe smaller volume preparations such as MOVIPREP (a slightly hypertonicsolution also based on PEG), SUPREP (based on sulfate as the osmoticagent) and Phosphosoda (based on phosphate). The larger volumepreparations require ingestion of up to 4 liters (about 1 gallon) ofsolution (Davis et al. 1980; Fordtran et al. 1990). While recognized asthe safest products, these large-volume preparations produce patientdiscomfort often resulting in poor compliance due to the large volume ofsalty tasting solution that must be consumed. An early innovationattempting to solve this problem was the development of a split dosehypertonic solution. The product, sold under the name Phosphosoda, wasrecognized to produce excellent bowel cleansing and required theingestion of only a small volume of solution (Vanner et al. 1990). Theproduct was also made into tablets, sold under the name Osmoprep(Aronchick et al. 2000). Although these products enjoyed improvedpatient tolerance, because they were formulated using salts ofphosphate, they became associated with risk of renal failure due torenal calcium phosphate deposition (resulting from absorption of thephosphate anion) eventually prompting the FDA to issue a warningconcerning their use (USFDA Alert 2008). A further innovation was thedevelopment of an alternative hypertonic preparation based on a uniquecombination of three sulfate salts (Cleveland/Fordtran Patent). Approvedby FDA in 2010, SUPREP combined sulfate salts of sodium, potassium andmagnesium in such a manner as to balance or compensate for electrolytelosses and gains resulting from the copious diarrhea induced by theosmotically active sulfate anion without risk of renal calcification(Patel et al. 2009).

Development studies had shown that all three sulfate salts were requiredin the liquid formulation and that the SUPREP formulation producedcleansing diarrheal stool output similar to Phosphosoda (about 2400 ml:Cleveland/Fordtran Patent, Patel et al 2009). Generally, the threesulfate salts were balanced to provide the proper cleansing required fordiagnostic tests and to reduce the likelihood of electrolyte shifts.

The art has disclosed the use of non-aqueous formulations of sulfate andphosphate salts. However, these formulations have had drawbacksincluding insufficient cleansing and potential safety issues.Furthermore, sulfate salt formulations require large amounts of tabletsto cleanse the colon—a typically undesirable requirement for mostpatients—and are very unpalatable due to a highly salty taste (see,e.g., U.S. Pat. No. 6,103,268). Thus, the known non-aqueous formulationshave undesired characteristics that lead to unsatisfactory results in asubstantial population of patients.

As disclosed herein, the inventors have discovered that sulfate saltformulations require only two sulfate salts (sodium and magnesiumsulfate) relying upon the osmotic activity of sulfate anion which ispoorly absorbed. In addition, the inventors have discovered thatformulations lacking potassium sulfate can be formulated to preventelectrolyte gains or losses from the resulting cleansing diarrheafollowing ingestion of the tablets.

SUMMARY

Disclosed herein are compositions (alternatively, “formulations”) thatare effective and safe to cleanse the colon of a subject. Theformulations are effective to induce purgation of the colon and arefurther safe and effective to cleanse the colon. As used herein, theterm “purgation” means evacuation of a copious amount of stool from thebowels after oral administration of a composition. Furthermore,disclosed herein are methods for cleansing of the colon of a subject, aswell as methods for cleansing the colon. Also, disclosed herein aremethods of inducing purgation of the colon. The disclosed compositionsalso do not cause clinically significant electrolyte shifts and are thususeful for preparation of patients for diagnostic and surgicalprocedures. Such diagnostic and surgical procedures include, but are notlimited to, colonoscopy, sigmoidoscopy, radiographic examination, bowelsurgery, colon resection, and other colorectal procedures. Furthermore,the present compositions, formulations, and methods allow for treatmentof conditions such as fecal retention, constipation, and hard stools byproviding a formulation that can be used as a laxative when administeredin lower doses than used for colon cleansing.

Aspects of the compositions disclosed herein include a solid oral dosageformulation for cleansing a colon of a subject. As used herein, the term“a” means one or more unless specifically defined otherwise. In certainembodiments, the formulation comprises from about 30.0 grams to about40.0 grams of sodium sulfate, from about 4.0 grams to about 8.0 grams ofmagnesium sulfate, and from about 3.0 grams to about 5.0 grams ofpotassium chloride. In specific embodiments, the formulation comprisesfrom about 34.0 grams to about 36.0 grams of sodium sulfate, about 5.0grams to about 8.0 grams of magnesium sulfate, and about 3.5 grams toabout 4.5 grams of potassium chloride. As used herein, the term “about”means within +/−10% of the recited value. For instance, about 2.0 wouldcover from 1.8 to 2.2. In more specific embodiments, the formulationcomprises either about 34.6 grams or about 35.5 grams of sodium sulfate,either about 5.4 grams or about 7.8 grams of magnesium sulfate, andeither about 3.7 grams or about 4.5 grams of potassium chloride. In someembodiments, the formulations comprise about 0.1 grams to about 1.0grams of sodium caprylate. In other embodiments, the formulationscomprise about 0.8 grams of sodium caprylate. In yet other embodiments,the formulations comprise about 0.168 grams of sodium caprylate.

In some embodiments, the sodium sulfate, magnesium sulfate, andpotassium chloride are compressed into about 14 to about 42 tablets. Inother embodiments, the disclosed formulation is compressed into about 18to about 38 tablets. In still other embodiments, the formulation iscompressed into about 20 to about 36 tablets, about 22 to about 34tablets, about 24 to about 32 tablets, or about 26 to about 30 tablets.In particular embodiments, the formulation is compressed into about 24tablets. In other particular embodiments, the formulation is compressedinto about 28 tablets. In other embodiments, the formulation is dividedinto two or more doses. In still other embodiments, each dose comprisesabout 7 to about 21 tablets. In yet more embodiments, each dosecomprises about 12 tablets or about 14 tablets.

In particular embodiments, the formulation delivers from about 450millimoles to about 550 millimoles of sodium, from about 40 millimolesto about 70 millimoles of magnesium, from about 50 millimoles to about60 millimoles of potassium, from about 50 millimoles to about 60millimoles of chloride, and from about 250 millimoles to about 350millimoles of sulfate. In certain embodiments, the formulation deliverseither about 493 millimoles or about 500 millimoles of sodium, eitherabout 45 millimoles or about 65 millimoles of magnesium, either about 50millimoles or about 60 millimoles of potassium, either about 50millimoles or about 60 millimoles of chloride, and either about 295millimoles or about 309 millimoles of sulfate.

In other embodiments, the formulation consists of about 35.5 grams orabout 34.6 grams of sodium sulfate, about 5.4 grams or about 7.8 gramsof magnesium sulfate, and about 3.7 grams or about 4.5 grams ofpotassium chloride. In more particular embodiments, the formulations arecompressed into about 24 tablets.

In still more embodiments, the formulation does not cause clinicallysignificant electrolyte shifts in the subject.

Additional aspects comprise a solid oral formulation for inducingpurgation of a colon of a subject. In certain embodiments, theformulation comprises from about 17.0 grams to about 20.0 grams ofsodium sulfate, from about 2.0 grams to about 4.0 grams of magnesiumsulfate, and from about 1.5 grams to about 2.5 grams of potassiumchloride. In specific embodiments, the formulation comprises at leastabout 17.3 grams of sodium sulfate, at least about 2.7 grams ofmagnesium sulfate, and at least about 1.8 grams of potassium chloride.

In certain embodiments, the formulation is compressed into tablet form.The formulation can also be compressed into capsules, caplets, and othersolid dosage units that can be administered to a patient. Such dosageforms contain predetermined amounts of active ingredients, and can beprepared by methods of pharmacy well known to those skilled in the art(Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, EastonPa. (1990)). In other embodiments, the formulation comprises about 12tablets.

In yet other embodiments, the formulation does not cause clinicallysignificant electrolyte shifts in the subject. In further embodiments,the formulations dissolve sufficiently to cause a purgative effect andin sufficient doses to cleanse the colon.

Further aspects include a method of cleansing a colon of a subject. Themethod comprises administering a solid oral formulation to the subject.In some embodiments, the solid oral dosage formulation comprises fromabout 30.0 grams to about 40.0 grams of sodium sulfate, from about 4.0grams to about 8.0 grams of magnesium sulfate, and from about 3.0 gramsto about 5.0 grams of potassium chloride. In specific embodiments, theformulation comprises from about 34.0 grams to about 38.0 grams ofsodium sulfate, about 4.0 grams to about 8.0 grams of magnesium sulfate,and about 3.0 grams to about 5.0 grams of potassium chloride. As usedherein, the term “about” means within +/−10% of the recited value. Forinstance, about 2.0 would cover from 1.8 to 2.2. In more specificembodiments, the formulation comprises either about 34.6 grams or about35.5 grams of sodium sulfate, either about 5.4 grams or about 7.8 gramsof magnesium sulfate, and either about 3.7 grams or about 4.5 grams ofpotassium chloride. In some embodiments, the formulations comprise about0.2 grams to about 1.0 grams of sodium caprylate. In other embodiments,the formulations comprise about 0.8 grams of sodium caprylate. In someembodiments, the formulations comprise from about 1.6 grams to about 2.1grams of polyethylene glycol. In other embodiments, the formulationscomprise from about 1.0 grams to about 3.0 grams of polyethylene glycol.In particular embodiments, the polyethylene glycol is PEG-8000. Themethods allow for administration of the solid oral formulation such thatthe formulation induces purgation of the subject's colon such that thecolon is cleansed of fecal matter.

In some embodiments, the amount of bisacodyl administered to the subjectis from 5.0 mg to about 15.0 mg. In other embodiments, the solid oralformulation is administered with or further comprises from about 60.0grams to about 100 grams of PEG. For instance, the PEG can beco-administered as a solution with the solid oral formulation.

In still other embodiments, the solid oral formulation is in the form ofa powder, tablet, or sachet. In still further embodiments, theformulation does not cause clinically significant electrolyte shifts ina subject. One of ordinary skill in the art will recognize that aclinically significant event must have a genuine, noticeable, andunexpected effect on the life of a subject. Mere changes in electrolytelevels outside of a given range in a single patient or small group ofpatients will not rise to the level of a clinically significant event.Rather, a clinically significant event is one that substantially effectsthe life of a subject. A clinically significant electrolyte shift canalso be found when the mean electrolyte levels of a population shiftoutside of the normal range for the population of patients, not just inan individual patient or small group of patients within the population.Furthermore, one of ordinary skill will recognize that an event must beunexpected as well. For instance, the disclosed formulations aredesigned to purge the colon and such formulations would be expected tocause diarrhea, in some cases, vomiting, and dehydration. These eventswould not be clinically significant events due to their being expectedin some individuals.

In some embodiments, the pharmaceutical tablet composition furthercomprises one or more soluble excipients. In other embodiments, the oneor more excipients soluble in aqueous solutions are selected from thegroup consisting of binders, lubricants, glidants, disintegrants, andcombinations thereof. In still other embodiments, the one or moresoluble excipients are selected from the group consisting of micronizedpolyethylene glycol, sodium dodecyl sulfate, sodium lauryl sulfate,sodium stearyl fumarate, sodium benzoate, sodium caprylate, andcombinations thereof.

In some embodiments, the one or more soluble excipients are selectedfrom the group consisting of binders, lubricants, glidants,disintegrants, and combinations thereof. In other embodiments, the oneor more water soluble excipients are selected from the group consistingof polyethylene glycol, such as PEG-8000, sodium dodecyl sulfate, sodiumlauryl sulfate, sodium benzoate, sodium stearyl fumarate, sodiumcaprylate, and combinations thereof.

In certain embodiments, the formulation is administered on the same dayas a surgical procedure. In yet more embodiments, the formulation isadministered the day before a surgical procedure. In other embodiments,the formulation is administered as a split dose. In particularembodiments, the formulation is provided as a half dose the day beforethe procedure and a half dose the day of the procedure.

DETAILED DESCRIPTION

1. Tablet Cleansing Formulations

Disclosed herein are pharmaceutical tablet formulations useful forinducing purgation of the colon and further useful for cleansing thecolon. As used herein, the terms “tablet,” “tablet composition,” and“tablet formulation” each individually refer to a composition orformulation that contains a mixture of active pharmaceutical ingredientsand/or excipients (i.e., inactive ingredients) that can be formed into asolid dosage unit by way of its designed and inherent compactability,flowability, and adherence characteristics. Exemplary formulations canbe compressed consecutively and continuously, manufactured or produced,into dosage units using compression style tableting equipment.

The disclosed compositions and formulations produce dosage units that,when manufactured, exhibit consistent and acceptable physicalcharacteristics. The dosage units must also be appropriate for ingestionby a patient and meet desirable and measurable pharmaceuticalperformance and quality attributes. Aspects of the compositionsdisclosed herein comprise sodium sulfate. In some embodiments, thesodium sulfate is selected from the group consisting of anhydrous sodiumsulfate and sodium sulfate hydrates such as sodium sulfate decahydrate.

As used in certain aspects disclosed herein, sodium sulfate allows forpurging of the colon of a patient to achieve cleansing. In particularuses, sufficient sodium sulfate to participate in cleansing the colon isadministered over a period of time (e.g., six or more hours, 12 or morehours, and up to 24 hours). Without being held to any particular theory,the sulfate salts are poorly absorbable and cause water to flow into theintestine when provided in the intestine in sufficient quantities.Poorly-absorbable salts exhibit limited uptake from the intestine andthat the salts remaining in the intestine cause water to flow into theintestines. Accordingly, the pharmaceutical tablet formulationsdisclosed herein can be administered with water to induce purgation ofthe colon of a subject (e.g., patient) and such compositions can be usedto cleanse the colon when administered in sufficient quantities. Afurther advantage of the presently disclosed compositions is that suchcompositions do not cause clinically significant electrolyte shifts whenadministered in sufficient quantities to induce purgation of the colonand balanced with other salts as disclosed herein. In some embodiments,the electrolyte shifts that the disclosed formulations avoid are shiftsin sodium, magnesium, potassium, and chloride. The disclosedformulations avoid such shifts by providing sufficient amounts ofsodium, magnesium, and potassium cations to avoid shifting the levels ofthese cations in a subject taking the compositions.

The formulations disclosed herein can be administered as 20 to 30tablets to cleanse the colon, and some embodiments, administered asabout 24 tablets and about 28 tablets. However, one of ordinary skill inthe art will recognize from this disclosure that the formulations can beadministered as about 14 to about 42 tablets, about 18 to about 38tablets, about 20 to about 36 tablets, about 22 to about 34 tablets,about 24 to about 32 tablets, or about 26 to about 30 tablets. Eachtablet can comprise from about 0.6 grams of sodium sulfate to about 3.0grams of sodium sulfate. When a subject (e.g., a patient) isadministered a cleansing dose of the formulations, the total amount ofsodium sulfate is from about 25.0 grams to about 40.0 grams. Inparticular embodiments, the total amount of sodium sulfate is about 35.0grams. In more particular embodiments, the sodium sulfate amounts areeither 35.5 grams or about 34.6 grams. Subjects administered sodiumsulfate, a cleansing dose of the formulations can deliver from about 490millimoles to about 505 millimoles of sodium and from about 290millimoles to about 310 millimoles of sulfate.

It should be noted that the cleansing dose can be administered in two ormore administrations. In certain embodiments, the cleansing dose isadministered in two doses to a subject over a period of at least sixhours. The cleansing dose can also be administered in two doses over aperiod of at least eight hours, at least ten hours, at least twelve, orup to 24 hours. The cleansing dose can also be administered in three ormore doses over a period of at least six hours, at least eight hours, atleast ten hours, at least twelve, or up to 24 hours.

Aspects of the pharmaceutical tablet compositions disclosed hereinsodium sulfate can comprise at least 70% (w/w) of the tabletcomposition. In some embodiments, the sodium sulfate comprises at least60% (w/w) of the tablet composition. In other embodiments, the sodiumsulfate comprises at least 50% (w/w) of the tablet composition. Inparticular embodiments, the pharmaceutical tablet compositions comprisefrom about 65% to about 75% sodium sulfate. In some embodiments, thepharmaceutical tablet compositions comprise at least about 70% sodiumsulfate.

As described herein, the formulation comprising sodium sulfate comprisesan effective amount of magnesium sulfate. It should be noted that bothmagnesium and sulfate contribute to purgation that allow theformulations to help cleanse the colon of a subject. In certainembodiments relating to cleansing the colon, the disclosed formulationscan be administered such that the subject receives from about 4.0 gramsto about 8.0 grams of magnesium sulfate. In particular embodiments, theplurality of tablets comprise from about 5.0 grams to about 8.0 grams ofmagnesium sulfate. In more particular embodiments, the formulationscomprise either about 5.4 grams or about 7.8 grams of magnesium sulfate.

As disclosed herein, the formulations comprise sufficient magnesiumsulfate (e.g., magnesium sulfate tribasic anhydrous) to induce purgationof the colon. Magnesium is poorly absorbed by the intestines of asubject and contributes to the osmotic diarrheal action of the tablets.When the formulations are administered to subjects with the amounts ofmagnesium sulfate and sodium sulfate disclosed herein, the formulationswill induce purgation of the colon and when administered in sufficientamounts will lead to cleansing of the colon. For instance, when thetablets are administered over a period of up to 24 hours, the subjectwill have sufficient diarrhea to cleanse the colon of stool.

Aspects of the disclosed formulations also include potassium chloride.The amount of potassium chloride in the formulations can be from aboutfrom about 2.0 grams to about 5.0 grams. In particular embodiments, theformulations comprise from about 3.5 grams to about 5.0 grams ofpotassium chloride. In more particular embodiments, the formulationscomprise either about 3.7 grams or about 4.5 grams of potassium sulfate.

As noted above, the formulations can be administered in tablet form innumbers from about 24 tablets, about 28 tablets, about 14 to about 42tablets, about 18 to about 38 tablets, about 20 to about 36 tablets,about 22 to about 34 tablets, about 24 to about 32 tablets, or about 26to about 30 tablets. It should be recognized that each tablet thereforecomprises a subdivided amount of magnesium sulfate from the formulationtotal. In other words, if the formulation is divided into 24 tablets,each tablet comprises from about 1.04 grams to about 1.66 grams ofsodium sulfate, from about 0.16 grams to about 0.333 grams of magnesiumsulfate, and from about 0.08 grams to about 0.20 grams of potassiumchloride.

As noted herein, the disclosed formulations can be tablets that arecombinations of sodium sulfate, magnesium sulfate, and potassiumchloride. The combination of salts and amounts of each salt have beendeveloped to avoid the clinically significant electrolyte shifts foundwith the use of other solid and hypertonic formulations. This balance ofsalts allows for inducing of osmotic diarrhea (i.e., purgation) whilereducing the clinically significant gains or losses of electrolytes(i.e., shifts of electrolytes) during the process of purgation.

The pharmaceutical tablet formulations can further comprise one or moreexcipients. The one or more excipients (e.g., soluble) are selected fromthe group consisting of binders, lubricants, glidants, disintegrants,and combinations thereof. Exemplary excipients include binders such ascopolyvidone, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hypromellose, lactose anhydrous, povidone, andpolyethylene oxide. Other exemplary excipients include emulsifyingagents such as hydroxypropyl cellulose, polaxamer 407, and sodium laurylsulfate. Additional exemplary excipients include soluble lubricants.Water-insoluble lubricants such as magnesium stearate, stearic acid,hydrogenated vegetable oil, and glyceryl palmitostearate leave insolubleresidues in the colon that interfere with diagnostic visualization ofthe colon. Accordingly, the disclosed compositions utilize water-solublelubricants such as polyethylene glycol, polaxamer 407, sodium laurylsulfate, sodium benzoate, sodium dodecyl sulfate, sodium caprylate, andsodium stearyl sulfate. Further exemplary excipients includedisintegrants such as citric acid, croscarmellose sodium, and povidone.In certain embodiments, the tablet formulations disclosed hereincomprise sodium caprylate in an amount from about 0.1 grams to about 1.0grams. In particular embodiments, the tablet formulations comprise about0.442 grams of sodium caprylate or 0.84 grams of sodium caprylate, suchas embodiments in which the formulations comprise 24 tablets ofcompressed sodium sulfate, magnesium sulfate, and potassium chloride.

In some embodiments, the pharmaceutical tablet formulations compriseonly a very minimal amount of water-soluble excipients. The benefitbeing that these tablets will dissolve clearly leaving no insolubleresidue in the gastrointestinal tract. In particular embodiments, theone or more soluble excipients are selected from the group consisting ofpolyethylene glycol, sodium dodecyl sulfate, sodium lauryl sulfate,sodium stearyl fumarate, sodium benzoate, sodium caprylate, andcombinations thereof. In certain embodiments, the pharmaceutical tabletcompositions comprise less than or equal to 5% (w/w) excipients in thetotal tablet compositions. In other embodiments, the pharmaceuticaltablet compositions comprise less than or equal to 10% (w/w) excipientsand alternatively less than or equal to 5% (w/w) excipients in the totaltablet compositions.

Additional aspects of the disclosed formulations include the addition ofother agents to assist in the cleansing of the colon of a subject. Suchadditional agents can be included in the tablet formulations comprisingsodium sulfate, magnesium sulfate, and potassium chloride.Alternatively, the additional agents can be separate tablets orreconstituted solutions that are provided with the disclosed tabletformulations. Examples of additional agents include, but are not limitedto, bisacodyl, picosulfate, and polyethylene glycol (“PEG”). In someembodiments, each tablet formulation comprises from about 1.0 grams ofPEG to about 5.0 grams of PEG. In some embodiments, each tabletformulation comprises from about 1.0 grams to about 3.0 grams of PEG. Inother embodiments, each tablet formulation comprises from about 1.6grams to about 2.1 grams of PEG. In particular embodiments, theformulations comprise about 2.08 grams of PEG. In more particularembodiments, the PEG is PEG-8000 in the tablet formulation or PEG-3350in the reconstituted solution.

In particular embodiments, the formulations comprise bisacodyl, which isa well-known stimulant laxative (Stiens et al. (1998) Spinal Cord.36(11): 777-781). When bisacodyl is used with the disclosedformulations, the cleansing dose of the disclosed formulations can bedecreased by one-third or one-half of the dose disclosed herein forcleansing.

In particular embodiments, the tablet formulations are administeredalong with a solution comprising PEG. In certain embodiments, the PEGsolution is reconstituted from bulk powder PEG diluted in water. Forinstance, a subject can be administered from about 4 to 10 tablets ofthe formulation to induce purgation. The subject is also administered areconstituted solution of PEG, where the PEG in an amount from about50.0 grams to about 150 grams is reconstituted in 250 ml to 500 ml ofwater. In some embodiments, from about 60 to about 100 grams of PEG isreconstituted in 250 ml to about 500 ml of water.

It has also been discovered that commercially available sodium sulfatecan form slow dissolving crystals. Such slow dissolving crystals canprevent a pharmaceutical tablet composition from dissolving sufficientlyto have the desired effect on a subject. In certain embodiments, sodiumsulfate particles having a diameter of less than 150 μm are removedprior to formulating pharmaceutical tablet compositions. In particularembodiments, the pharmaceutical tablet composition is substantially freeof sodium sulfate particles of less than 150 μm. In some embodiments,fines of a diameter of less than 150 μm are added back to the sodiumsulfate that is substantially free of such crystals. In particularembodiments, the fines comprise 10% (w/w) of the sodium sulfate. Inparticular embodiments, the sodium sulfate particles in thepharmaceutical tablet compositions comprises about 90% (w/w) particleshaving a diameter of between about 150 μm and about 700 μm and about 10%(w/w) fines (i.e., particles having a diameter of less than 150 μm) thatare added back to the sodium sulfate. It is believed that the addedfines increase hardness such that there is no picking. Furthermore, thecompositions do not need additional lubricants beyond the levelsdisclosed herein. Additionally, the presently disclosed compositionsallow for a wider hardness range for the compositions and a more robustformulation.

The pharmaceutical tablet formulations can be tableted using standardproduction style equipment and techniques (Bogda, Michael J. Ch. 260,“Tablet Compression: Machine Theory, Design, and ProcessTroubleshooting” in Encyclopedia of Pharmaceutical Technology, ThirdEdition, 2006). In other embodiments, the pharmaceutical tabletformulation is encapsulated.

The coating can also be a film that coats the tablet. Film coats aremost commonly deposited on the tablets by spraying a thin uniform layeron the tablet. Polymers used in film coats include sucrose,hypromellose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose,carboxymethylcellulose sodium, hydroxypropyl cellulose, polyethyleneglycol, and ethylcellulose. In particular embodiments, the coatingquickly dissolves without affecting disintegration and/or dissolution ofthe tablet composition. In further embodiments, the coating does notleave a residue that affects visualization of the colon. In certainembodiments, the tablet formulation comprises a coating that comprisesKollicoat IR and water.

It is understood that the formulations disclosed herein can dissolve inbuffers, body fluids, or physiological solutions. The disclosedformulations can dissolve sufficiently to allow for purgation of thecolon and in sufficient amounts, cleansing of the colon. Suchformulations can also disintegrate and the determination of tabletdisintegration can be accomplished using in vitro test methods providedin the United States Pharmacopoeia (see e.g., United StatesPharmacopoeia, Vol. 36 <711> Dissolution, pages 307-313, applyingApparatus 2 (Paddle Apparatus)). In particular embodiments, thedisclosed tablet compositions cause little or no turbidity whendissolved in solution. For instance, when dissolved in solution, thetablet compositions will generate solutions having turbidities of 0 to15 Nephelometry Turbidity Units (NTU). In more particular embodiments,the solutions will have turbidities of about 0.1 to about 10 NTU or 0.5to 5 NTU. In even more particular embodiments, the solutions will haveturbidities of about 0.1 to about 20 NTU.

2. Purgative Formulations

In particular embodiments, the formulations are administered in anamount sufficient to induce purgation, the “purgative dose.” In certainembodiments, the purgative formulations comprise a plurality of tabletssuch as the pharmaceutical tablet compositions disclosed herein. Theplurality of tablets comprise an effective amount of sodium sulfate,magnesium sulfate, and potassium chloride to induce purgation of thecolon of a subject.

In certain embodiments, the purgative formulations are a plurality oftablets (such as the pharmaceutical tablet formulations disclosedherein). In particular embodiments, the purgative formulation comprisesan effective amount of sodium sulfate, magnesium sulfate, and potassiumchloride to induce purgation of the colon. In some embodiments, theeffective amount of sodium sulfate comprises at least 60% (w/w) of thetotal weight of the formulation and can be up to 80% (w/w) of the totalweight of the formulation. The effective amount of sodium sulfate incombination with magnesium sulfate should be sufficient to inducepurgation of the colon. The avoidance of clinically significantelectrolyte shifts can be accomplished by the proper balance ofpotassium chloride, magnesium sulfate, and sodium sulfate. Suchbalancing of cations to avoid clinically significant electrolyte shiftshas been disclosed in U.S. Pat. No. 6,946,149, the contents of which areincorporated herein by reference.

In more particular embodiments, the plurality of tablets comprises about7 to about 21 tablets. In particular embodiments, the plurality oftablets comprises about 8 to about 14 tablets. In some embodiments, theplurality of tablets comprises 12 tablets. In some embodiments, theformulations are administered in amounts that purge the colon of asubject. The pharmaceutical tablet compositions disclosed hereincomprise an effective amount of sodium sulfate and magnesium sulfate toinduce purgation of the colon.

When the formulations are administered to induce purgation of the colon,the formulations comprise from about 8.0 grams to about 25.0 grams ofsodium sulfate. In specific embodiments, the formulation comprises atleast about 11.0 grams to at least about 20.0 grams of sodium sulfatewhen administered to induce purgation. In more specific embodiments, theformulation comprises from about 17.0 grams to about 17.7 grams whenadministered to induce purgation. The purgative dose can be administeredin an amount of about 9 to about 11, about 8 to about 12, or about 5 toabout 15 tablets.

When the formulations are administered as a purgative dose, the subjectreceives from about 1.0 grams to about 6.0 grams of magnesium sulfate.In specific embodiments, the formulation comprises at least about 2.0grams to at least about 4.0 grams of magnesium sulfate when administeredto induce purgation of the colon. In more specific embodiments, theformulation comprises from about 2.7 grams to about 3.9 grams ofmagnesium sulfate when administered to induce purgation of the colon. Asdisclosed above, the purgative dose can be administered in an amount ofabout 9 to about 11, about 8 to about 12, or about 5 to about 15tablets.

As noted herein, the formulations can be administered as a purgativedose of about 9 to about 11, about 8 to about 12, or about 5 to about 15tablets. When administered as a purgative dose, the subject isadministered from about 1.0 grams to about 4.0 grams of potassiumchloride. In specific embodiments, the formulation comprises at leastabout 1.6 grams to at least about 2.5 grams of potassium chloride whenadministered to induce purgation of the colon. In more specificembodiments, the formulation comprises from about 1.8 grams to about 2.3grams of potassium chloride when administered to induce purgation of thecolon.

In particular embodiments, the formulation delivers at least about 200millimoles to at least about 300 millimoles of sodium, at least about 20millimoles to at least about 40 millimoles of magnesium, at least about20 millimoles to at least about 40 millimoles of potassium, at leastabout 20 millimoles to at least about 40 millimoles of chloride, and atleast about 100 millimoles to at least about 200 millimoles of sulfateto the subject when administered as a purgative dose.

As disclosed herein, the total dose to cleanse the colon can beadministered in a split-dose with one dose the day before a diagnosticor surgical procedure and a second dose on the day of the procedure, asplit dose the day before the procedure, a split dose on the day of theprocedure, or as a single dose given the day before or the day of theprocedure. During the cleansing protocol, each dose would cause apurgation in the subject.

3. Methods of Administering Purgative Formulations and PharmaceuticalTablet Compositions

Disclosed herein are methods of administering the purgative formulationsand pharmaceutical tablet compositions. Aspects of the disclosed methodscomprise administering to the subject a purgative formulation comprisinga plurality of pharmaceutical tablet compositions. In certainembodiments, the purgative formulation comprises an effective amount ofat least one sulfate salt.

In particular embodiments, the purgative formulations are administeredin an amount effective to induce purgation of the colon. Whenadministered to a subject, the purgative formulations provide a dose ofsulfate and magnesium salts to the subject effective to purge the colon.In still other embodiments, the purgative formulation is provided to thesubject such that the dose of sulfate and magnesium salts effectivelycleanses the colon.

The methods disclosed herein further comprise orally administering assmall of a quantity of tablets as needed to a patient. In certainembodiments, the plurality of tablets administered to the subject is atleast 20 tablets. In some embodiments, the plurality of tabletsadministered to the subject is at least 30 tablets. In otherembodiments, the plurality of tablets administered to the subject is 12tablets. In particular embodiments, the plurality of tablets isadministered to the subject in an amount of 24 tablets. In moreparticular embodiments, the plurality of tablets is 28 tablets. In yetmore embodiments, the plurality of tablets administered to the subjectis 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, or 42 tablets.

In some embodiments, the methods comprise administering a plurality oftablets in which each tablet in the plurality comprises only sodiumsulfate, magnesium sulfate, and potassium chloride. In theseembodiments, the multiplicity of tablets comprises sodium sulfate in anamount from about 10.0 grams to from about 40.0 grams of sodium sulfatedepending on the desired effect (i.e., purgation, laxation, orcleansing). The plurality of tablets also comprises magnesium sulfate inan amount from about 1.0 grams to about 10.0 grams of magnesium sulfatedepending on the desired effect (i.e., purgation, laxation, orcleansing). The plurality of tablets can comprise potassium chloridefrom about 1.0 grams to about 8.0 grams, depending on the desired effect(i.e., purgation, laxation, or cleansing).

Additionally, the disclosed formulations can be administered with asufficient quantity of liquid to ease swallowing of the tablets and toavoid dehydration caused by the dose of sulfate salts administered tothe subject. One of ordinary skill in the art would recognize thatdehydration is a possible expected adverse event when taking thedisclosed formulations with insufficient water. In certain embodiments,the liquid is a clear liquid, such as water. In particular embodiments,the total volume of liquid administered to the subject is from about 500ml to about 1.0 liters. When the purgative formulation is administeredto cleanse the colon, the volume of liquid administered to the subjectcan be adjusted to prevent dehydration (e.g., the volume of liquid canbe increased up to 2.0 liters or more depending on the needs of theparticular subject). In particular embodiments, the liquid consumed intwo hours or less after ingesting the purgative formulation.

In certain embodiments, the plurality of tablets are split into two ormore portions. For instance, the plurality of tablets is split into twoportions, three portions, or four or more portions. The only limitationto the splitting of the plurality of tablets is to insure that thesubjects experience a purgation. One of ordinary skill in the art willunderstand that when an additional stimulant laxative such as bisacodylor picosulfate is used, the dose of the disclosed formulations necessaryto induce purgation will likely be lower than the amount of thedisclosed formulation necessary when not using a stimulant laxative.Notwithstanding the use of stimulant laxatives, the portions can beadministered over a period of two or more hours, four or more hours, sixor more hours, eight or more hours, ten or more hours, twelve or morehours, 14 or more hours, 16 or more hours, 18 or more hours, 20 or morehours, 22 or more hours, or 24 or more hours. Each portion of tablets issufficient to induce purgation of the colon.

In some embodiments, the plurality of tablets is split into twoportions. In such embodiments, the first portion is administered andallowed to induce purgation. At some point after purgation, the secondportion is administered and allowed to induce purgation. As used herein,the term “allowed” means that a subject or physician does not interveneto cease the procedure. After the second purgation, the subject canundergo a diagnostic procedure such a colonoscopy. In these embodiments,the administration of the two portions is split by two or more hours,four or more hours, six or more hours, eight or more hours, ten or morehours, twelve or more hours, 14 or more hours, 16 or more hours, 18 ormore hours, 20 or more hours, 22 or more hours, or 24 or more hours. Insome embodiments, the first portion can be administered the eveningbefore a diagnostic or surgical procedure such as a colonoscopy and thesecond portion can be administered on the day of a colonoscopy.

In yet another embodiment, the plurality of tablets is split into two ormore doses and the doses are administered on the same day. When asplit-dose regimen is performed on a single day, each portion of theregimen can be administered with about one hour to about ten hoursbetween administrations of the doses such that the doses are alladministered on the same day.

In particular embodiments, the method further comprises administering avolume of water to a subject after taking a portion of tablets. Thevolume of water is sufficient to allow the subject to consume thetablets. The subject is then instructed to drink additional water over aperiod of one to three hours. The volume of water is from about 500 mlto about 6.0 liters. One of ordinary skill in the art will recognizethat larger or smaller volumes of water may be required depending on theage, health, or other factors present for a patient. It is typical forthe subject to be instructed not to consume food or colored liquidsduring the course of the regimen.

In certain embodiments, the tablets are administered in a single dose of20 to 30 tablets. For instance, the tablets can be administered in adose of 24 tablets. In such embodiments, the tablets are provided with asufficient quantity of water to allow the subject to consume thetablets. In particular embodiments, an additional 500 ml to 2.0 litersof water (in some embodiments, 1.0 to 1.5 liters of water) are consumedby the patient over a period of one to three hours after consuming thetablets. In this full-dose regimen, the regimen can be performed theevening before a diagnostic or surgical procedure or the day of theprocedure.

4. Methods of Manufacture

Disclosed herein are methods of manufacturing the disclosedcompositions. Aspects of the methods include combining one or more watersoluble salts, one or more water soluble binders, and one or more watersoluble lubricants. The disclosed methods include blending the one ormore salts using blender such as a standard slant cone or cone blender(GEMCO, Middlesex, N.J.). Other types or classifications of blendingequipment may be utilized in place of the cone style blending equipmentwhere appropriate. In certain embodiments, the salts are added to theblender and tumbled for between about 10 and about 60 minutes.

In particular embodiments, the one or more salts, one or more binders,and one or more lubricants requires particle size reduction ormodification. Such techniques are known to those of ordinary skill inthe art. In particular embodiments, broadcasting of one or morecomponents of the disclosed formulations together prior to blending isrequired to facilitate the blending process. In particular embodiments,one or more binders, such as PEG-8000, are added and blended untilcompletely dispersed. In particular embodiments, a lubricant, such assodium caprylate, is added after the binder and blended forapproximately 1 to 5 minutes.

Aspects of the disclosed methods include transferring the blend to astandard rotary style Tablet Press (36 Station Stokes 454). Typicalrotary style tablet presses consist of upper and lower punches, dies,hopper, feed frame and a die table with appropriate controls and cams tocompress an accurate and consistent amount of formulation into a tablet.In some embodiments, the formulation is fed to a hopper. The feed framedelivers the formulation from the hopper to the dies. In someembodiments, the lower punch is set to a certain position in the die todetermine the desired fill or tablet weight. As the machine rotates thecorresponding upper punch is directed into the die. The method alsocomprises the press continues its rotation the upper and lower punchestravel through pre and final compression stations where compressionrollers apply specific amounts of tonnage or pressure forcing thepunches together within each die to form a tablet. As the presscontinues in its rotation the tablet is ejected from the die.

In particular embodiments, tablet samples are evaluated and measured forhardness, weight, and thickness to ensure the tablets meet predeterminedand required tablet characteristic during compression. Pharmaceuticaltablets are made, usually, to conform or to meet USP dissolution anddisintegration specifications.

Tablets are then coated using coating equipment (Thomas EngineeringInc., Hoffman Estates, Ill.). In certain embodiments, the coat is amixture of water, Kollicoat IR, and PEG. In particular embodiments,tablets are loaded into the coating pan and brought up to temperatureand then the pan rotates tumbling the tablets in preparation forcoating. A metering pump can be used to deliver the coating solution toair atomizing nozzles. The volume of spray solution and the PSI of thecompressed air delivered to the atomizing nozzles can be adjusteddepending on the needs of one of ordinary skill in the art. The nozzlesare positioned to spray the atomized solution directly on to thetumbling tablets. In some embodiments, temperature controlled air isblown through the tablets as they tumble helping to apply the atomizedspray while drying the coating solution onto each tablet. Once theappropriate amount of coating has been applied to the tablets, thetablets are dried for a time and then moved into packaging.

EXAMPLES 1. Example 1. Core Formulation

Tablets according to the embodiments described herein were made asfollows. Each batch was made using the following amounts of activepharmaceutical ingredients and excipients. The weight of each activepharmaceutical ingredient and excipient per 24 tablets is also provided(Table 1).

TABLE 1 Tablet Ingredients (full dose) Ingredient 4700-8 4700-10 4700-12(g) 24 tabs 24 tabs 24 tabs Na₂SO₄ 35.5 34.6 35.5 MgSO₄ 5.4 7.8 5.4 KCl4.5 3.7 4.5 NaCaprylate 0.844 0.844 0.168 PEG-8000 1.60 1.60 2.080

Table 2 shows the ingredients contained in the FDA approved comparatorproducts. Tables 3 and 4 show the composition (in mM) of the tabletformulations and comparator products, respectively.

TABLE 2 FDA Approved Prep Ingredients (full dose) Ingredient GoLYTELYNuLYTELY MoviPrep (g) SUPREP 4 L 4 L 2 L PEG 0 236.0 420.0 200.0 Na₂SO₄35.0 22.74 0 15.0 K₂SO₄ 6.26 0 0 0 MgSO₄ 3.2 0 0 0 KCl 0 2.97 1.48 2.03NaCl 0 5.86 11.2 5.38 NaHCO₃ 0 6.74 5.72 0 NaAscorbate 0 0 0 11.8NaCaprylate 0 0 0 0 Ascorbate 0 0 0 9.4 Malic acid 0.63 0 0 0 Citricacid 0.63 0 0 0

TABLE 3 Tablet Prep Composition mM (full dose) Component 4700-8 4700-104700-12 (mmol) 24 tabs 24 tabs 24 tabs SO₄ 295 309 295 Na 500 493 500 K60 50 60 Mg 45 65 45 Cl 60 50 60

TABLE 4 FDA Approved Prep Composition mM (full dose) Component GoLYTELYNuLYTELY MOVIPREP (mmol) SURPEP 4 L 4 L 2 L PEG 0 70.4 125.2 59.7 SO₄308.9 160.1 0 86.1 Na 492.8 500.6 259.7 225.6 K 71.8 40.0 19.8 27.2 Mg26.6 0 0 0 Cl 0 140.2 211.4 119.3 HCO₃ 0 80.2 68.1 0 Ascorbate 0 0 0114.4 Citrate 6.3 0 0 0 Malic 4.7 0 0 0

2. Administration of Tablets and Formulations

i. Study Parameters

Various tablet formulations were evaluated and compared to FDA approved,marketed preparations (NuLYTELY, SUPREP, MOVIPREP) in an IRB approvedprotocol following an open label design study at a single site.Depending on the results from each formulation a new formulation wasdesigned and evaluated in a subsequent study, etc. Healthy normal malevolunteers 18-50 years of age were recruited. Each formulation ormarketed preparation was studied in groups of five volunteers at a time(one cohort). This was usually repeated to give a total of 10 or morevolunteers for each formula.

ii. Study Procedures

Study inclusion criteria required that volunteers were male between theages of 18 and 50 years; were in good health, as judged by a physicalexamination and review of medical history; and in the investigator'sjudgment the subject was mentally competent to sign an instrument ofinformed consent. All study volunteers signed an approved informedconsent document. Exclusion criteria were as follows:

-   -   1. Subjects known or suspected of having ileus, gastrointestinal        obstruction, gastric retention, bowel perforation, colitis,        megacolon, or colostomy.    -   2. Subjects with a history of clinically significant abnormal        ECGs or a clinically significant abnormal ECG at the screening        visit.    -   3. Subjects on salt-restricted diets, those with a history or        evidence of dehydration, ascites, electrolyte disturbances,        renal insufficiency, heart disease or who were taking diuretics        or other medications that affect electrolytes.    -   4. Subjects who had a bowel cleansing procedure within the past        month or who took a laxative within the past 5 days (120 hours)        before dosing.    -   5. Subjects who had participated in an investigational clinical,        surgical, drug, or device study within the past 90 days.    -   6. Subjects who had hepatitis B or C or were HIV positive at        screening.    -   7. Subjects who were drug users and/or use (have used) alcohol        to excess (more than 1 liter of beer per day or the equivalent        amount of any other alcoholic beverage).    -   8. Subjects who had any ongoing medical problems, including        diarrhea, or any subject who was scheduled for surgical        procedures or who had a history of clinically significant,        hepatic, neurologic, hematologic, endocrine, oncologic,        pulmonary, immunologic, psychiatric, cardiovascular disease, or        any other condition that, in the opinion of the Investigator,        would jeopardize the safety of the subject or impact the        validity of the study results.    -   9. Subjects who were allergic to any preparation components;        sodium sulfate, potassium sulfate or magnesium sulfate, citric        acid or citrate, malic acid, magnesium citrate, magnesium        chloride, sodium or potassium bicarbonate, potassium chloride or        polyethylene glycol-3350.    -   10. Subjects who had experienced severe chronic constipation        within the past 3 months.

A screening visit was performed within 28 days before confinement in theclinic where, following the informed consent process, study volunteersprovided their medical history and vital signs were obtained. Clinicallaboratory tests (including serology), a urine drug screen test(including alcohol), a physical examination and 12-lead ECG wereperformed.

In general, the tablet ingestion regimen in these studies employedadministration of 12 or 14 tablets for a total of two or, in some studygroups, three administrations given about 12 hours apart. Marketedpreparations were given as split dose following the same schedule astablets. Beginning on Day −1, groups of five subjects were confined tothe site for up to 48 hours, dependent on the dose schedule. Studyvolunteers were offered a light meal (breakfast or lunch depending uponthe regimen assigned) and were given water (in some experiments clearliquids were allowed) thereafter. Urinalysis, urine drug screen, bloodchemistry, hematology and coagulation tests were performed and reviewedto assure the volunteers met study entry criteria. A physicalexamination was also performed.

iii. Administration of Tablets

Beginning at 7 PM, on Day −1, the five study subjects begin taking their12 or 14 tablets (Dose 1) as quickly as possible along with 16 ounces ofwater to help swallow the pills. The entire administration (i.e. all 12or 14 tablets), together with the 16 ounces of water, was expected to beconsumed within approximately 20 minutes. Following completion of thefirst administration, subjects were instructed to drink two (2)additional servings of 16 ounces of water over the next hour at a rateof approximately 8 ounces of water every fifteen minutes. Blood wascollected for clinical chemistry, hematology, coagulation, and sulfatewithin 60 minutes before Dose 1 administration. Blood samples forclinical chemistry and serum sulfate analysis were also collected atinterval after the Dose, usually 4 and 6 hours. In later studies,subjects provided an expiratory air sample prior to tabletadministration and at 1, 2, 4, and 6 hours after each Dose to test forhydrogen and methane breath gases. Subjects collected all stool andurine voided beginning at approximately from the time of Dose 1 on Day−1 until prior to Dose 2 (the second administration) on Day 1 (Dose 1Pool).

Beginning at 7 AM, on Day 1, the subjects begin taking their secondadministration of 12 or 14 tablets (Dose 2) with 16 ounces of water asbefore. Following completion of Dose 2, subjects consumed two (2)additional servings of exactly 16 ounces of water over the next hour ata rate of approximately 8 ounces of water each fifteen minutes. Asbefore, blood was collected for clinical chemistry, hematology,coagulation, and sulfate within approximately 60 minutes before Dose 2and after the Dose, usually at 4 and six hours. In addition, (in laterstudies) subjects provided expiratory air samples prior to Dose 2 and at1, 2, 4, and 6 hours following the Dose. Subjects also collected allstool and urine voided beginning at approximately from the time of Dose2 on Day 1 until check-out (Dose 2 Pool). Subjects remained in theclinic for 8 hours after Dose 2, were offered a standard meal, andreleased after all procedures were completed.

Each bowel movement (BM) that was passed by a subject after each Doseuntil prior to the start of the next Dose or the end of study wascollected in separate labeled containers, one for each bowel movement.The time and weights of each BM were recorded. Stool solids weremeasured in the last BM that occurred on or before 4, 6, and 8 hours,and in the final BM sample following each Dose using the method of Patelet al., 2009. After the samples were weighed and aliquots obtained forstool solids, all individual BM samples from each Dose were pooled andanalyzed for osmolality and electrolytes (sodium, potassium, chloride,bicarbonate, phosphate, magnesium).

Assessments to determine the efficacy of a given formulation includedtotal stool volume (output), percent solids, fecal electrolyte balance,and blood electrolyte results. Beginning with Cohort 7, breath gaseswere measured as described. Volunteer tolerance to each preparation wasmonitored and safety was assessed using adverse event data. Descriptivestatistics (mean, standard deviation, ranges) were used to compare thedata.

3. Results

Cohorts of 5 male volunteers each were studied according to theprocedures described above. The protocol identifiers, cohorts,corresponding study subject numbers and formulas tested are shown belowin Table 5.

TABLE 5 Protocol Cohort: Prep Subject #s 4700-102 15 4700.8  174-1784700-102 16 4700.10 179-188 4600-101 1 SUPREP 56-60  800-103 1 SUPREP006-010  800-103 2 SUPREP 011-015 4600-101 1 NuLYTELY 001-005 4600-101 8NuLYTELY 036-040 4600-101 13 MoviPrep 061-065 4600-101 16 MoviPrep076-080

The intent of these studies was to develop a tablet formulation withsimilar stool volume output and percent stool solids (surrogates forcleansing) and stool electrolyte balance relative to the FDA approvedcommercial control preparations.

TABLE 6 Control Preparations Mean Stool Output Measure (SD) SUPREPNuLYTELY MOVIPREP N 15 10 9 Input 4547.5 (1048.0) 4050.0 (898.6) 4735.6(817.4) (water + prep) Stool 3386.0 (453.0) 3343.4 (930.4) 3031.7(620.7) Output

Table 6 shows the mean stool output results for each of the controlpreparations and shows the total amount of prep ingested plus anysupplemental water from the start of Dose 1 until the end of study andthe resulting total stool output. These preparations have been approvedby FDA for bowel cleansing for colonoscopy.

Table 7 shows the average of the stool percent solids measured aftereach dose of approved preparation.

TABLE 7 Control Preparations Mean Stool Percent Solids (SD) FormulaSUPREP NuLYTELY MOVIPREP N 15 10 9 Stool Solids 5.6 17.3 15.3 Dose 1(3.5) (12.0) (10.8) Stool Solids 2.4 3.1 5.4 Dose 2 (1.3) (1.8) (4.8)

As indicated in Table 7, a stool percent solids result less than 5%would be expected to correlate with acceptable colonoscopy cleansing,with 2.4% being the best achievable. Table 8, below, shows the meanstool electrolyte balance results for the three control preparations forsodium, potassium, chloride, magnesium and bicarbonate. For eachelectrolyte the total amount of electrolyte ingested from Dose 1 and 2of the prep is shown as “Input”. The total electrolyte excreted in thestool following both doses is shown as “Output”. The difference betweenInput and Output is shown as “Gain/Loss” and represents net absorption(Gain) or loss (secretion) of electrolyte from the intestinal tract. Asindicated in the table, the three commercial preparations differ withrespect to stool electrolyte balance under the conditions of thisprotocol.

TABLE 8 Control Preparations Mean (SD) Stool Electrolyte Balance ResultsNuLYTELY MOVIPREP SUPREP Formula (10) (9) (15) N 10   9   15   Na Input259.7  362.9  492.8  Na Output 207.9 (63.5) 340.2 (105.2) 543.1 (150.0)Na + Balance 51.9 (63.5) 22.7 (105.2) −50.3 (150.0) K Input 18.8 27.2 71.8 K Output 39.0 (14.8) 74.0 (61.9) 74.7 (25.0) K + Balance −19.1(14.8) −46.8 (61.9) −2.3 (25.0) Cl Input 210.4  119.3   0.0 Cl Output133.8 (46.5) 75.4 (36.1) 71.7 (22.1) Cl + Balance 76.6 (46.5) 43.9(36.1) −71.7 (22.1) Mg Input  0.0 0.0 26.6 Mg Output 5.5 (2.9) 8.7 (4.3)26.6 (8.9) Mg + Balance −5.5 (2.9) −8.7 (4.3) 0.004 (8.9) HCO₃ Input68.1 0.0  0.0 HCO₃ Output 64.6 (16.7) 35.1 (15.3) 47.0 (13.9) HCO₃ +Balance 3.5 (16.7) −35.1 (15.3) −47.0 (13.9)

For Table 8, a positive number in the Balance row of each indicates anet gain of the particular electrolyte, while a negative numberindicates a net loss of electrolyte. All three commercial preparationshad individually variable sodium movement which appears to be related tostool volume output, but overall sodium movement was neutral. SUPREP wasassociated with large chloride losses and NuLYTELY showed large gains.This is due to the absence of chloride in SUPREP and the large quantityof chloride in the NuLYTELY formulation. NuLYTELY also exhibited somepotassium loss. Mean results for blood electrolyte and anion gapmeasurements are shown in Table 9 for the control preparations.

TABLE 9 Control Preparations Mean (SD) Blood Electrolytes Analyte(normal range) Time SUPREP NuLYTELY MOVIPREP N 15 ^(a) 10 10 Na PreDose1 145.5 (1.7) 145.0 (2.2) 147.2 (2.1) (143-152 2-4 h post Dose 1 146.2(1.2) — 147.5 (1.2) mmol/L) 2-4 h post Dose 2 146.2 (1.6) 145.3 (2.3)146.6 (2.5) K PreDose 1 4.4 (0.3) 4.4 (0.3) 4.4 (0.3) (3.7-5.6 2-4 hpost Dose 1 4.7 (0.3) — 4.5 (0.3) mmol/L) 2-4 h post Dose 2 4.7 (0.4)4.6 (0.5) 4.7 (0.5) Cl PreDose 1 101.5 (1.6) 102.8 (1.6) 102.3 (2.7)(99-108 2-4 h post Dose 1 102.2 (1.8) — 103.7 (2.3) mmol/L) 2-4 h postDose 2 102.3 (1.8) 103.1 (1.5) 103.8 (3.0) Mg PreDose 1 2.1 (0.1) 2.1(0.1) 2.0 (0.1) (1.7-2.6 2-4 h post Dose 1 2.1 (0.1) — 2.0 (0.1) mg/dL)2-4 h post Dose 2 2.1 (0.1) 2.1 (0.1) 2.0 (0.1) HCO₃ PreDose 1 28.2(1.4) 27.7 (1.4) 26.6 (1.8) (23-33 2-4 h post Dose 1 28.3 (1.5) — 27.8(1.8) mmol/L) 2-4 h post Dose 2 27.8 (2.1) 28.0 (1.3) 26.5 (2.3) AnionPreDose 1 20.2 (1.2) 18.9 (1.7) 20.9 (2.2) Gap 2-4 h post Dose 1 20.3(1.4) — 21.0 (2.2) (3-11 2-4 h post Dose 2 20.8 (1.5) 18.8 (2.4) 21.0(2.2) mEq/L) ^(a) 15 subjects for PreDose 1, and 2-4 hours post dose 1.10 Subjects for 2-4 hours post dose 2

Table 10 shows the results of stool output measurements for the tabletformulations.

TABLE 10 Tablet Preparations Mean Stool Output ml (SD) Formula 8 10 12 N10 9 4 Input 5125.5 (1146.5) 5002.8 (1387.0) 4425.8 (652.7) (water +prep) Stool 2632.2 (1146.5) 2731.3 (423.1) 2888.5 (306.9) Output

Formulas 8, 10, and 12 produced stool output between 2600 ml and about2900 ml using 24 tablets of the formula. Although the stool output fromthe tablet formulations was somewhat less than that achieved by thecommercial controls, the average percent fecal solids of the lowestfecal solids result measured following each dose of tablets (a measureof colon cleansing) was the same or better, as shown in Table 11.

TABLE 11 Tablet Preparations Mean (SD) Stool Percent solids Formula 8 1012 N 10 10 5 Stool Solids 3.1 (2.7) 1.0 (1.4) 3.6 (2.9) Dose 1 StoolSolids 1.6 (1.0) 2.2 (1.3) 1.6 (0.3) Dose 2

Table 12 shows the stool electrolyte balance result for each tabletpreparation.

TABLE 12 Tablet Preparations Mean (SD) Stool Electrolyte Balance Resultsin mM 8 10 12 N 9 9 4 Na Input 504.9 493.7 Pending Na Output 461.5 501.7Pending (60.7) (143.5) NA 43.4 −8.0 Pending +Gain/−Loss (60.7) (143.5)Pending K Input 60.4 49.6 Pending K Output 58.0 65.2 Pending (14.1)(14.3) K 2.4 −15.6 Pending +Gain/−Loss (14.1) (14.3) Pending Cl Input60.4 49.6 Pending Cl Output 59.7 70.9 Pending (23.7) (54.8) Cl 0.7 −21.3Pending +Gain/−Loss (23.7) (54.8) Pending Mg Input 22.4 64.8 Pending MgOutput Pending Pending Pending Pending Pending Mg Pending PendingPending +Gain/−Loss Pending Pending Pending HCO₃ Input  0.0  0.0 PendingHCO₃ Output NA NA Pending NA NA Pending HCO₃ NA NA Pending +Gain/−LossNA NA

As shown in Table 12, sodium movement was individually variable(indicated by the large standard deviations). Overall, Formulas 8 and 10had sodium movements within the sample standard deviation, indicatingminimal loss or gain of this electrolyte. For potassium, Formulas 8 and10 had mean balances within the sample standard deviation with Formula 8showing the numerically smallest mean balances. With respect tochloride, Formulas 8 showed little or no movement.

Mean blood electrolyte results for the tablet formulations are shown inTable 13, below and reveal no important changes. Anion gap was improvedin Formulas 8 and 10.

TABLE 13 Mean (SD) Blood Electrolytes Tablet Preparations Analyte(normal Sample range) Period 8 10 12 N 10 10 4 Na PreDose 1 145.2 (1.2)146.5 (1.4) 147.3 (0.5) (143-152 4 h Dose 1 144.8 (1.8) 146.1 (1.4)147.8 (0.8) mmol/L) 4 h Dose 2 143.9 (1.3) 145.9 (1.4) 146.8 (1.5) KPreDose 1 4.3 (0.3) 4.3 (0.1) 4.3 (0.2) (3.7-5.6 4 h Dose 1 4.3 (0.2)4.3 (0.3) 4.7 (0.2) mmol/L) 4 h Dose 2 4.6 (0.3) 4.6 (0.3) 5.0 (0.4) ClPreDose 1 102.0 (1.5) 101.6 (1.7) 101.0 (0.8) (99-108 4 h Dose 1 101.7(2.5) 100.6 (2.5) 102.5 (1.1) mmol/L) 4 h Dose 2 101.0 (1.9) 101.0 (1.8)103.3 (1.3) Mg PreDose 1 2.0 (0.1) 2.1 (0.1) 2.1 (0.1) (1.7-2.6 4 h Dose1 2.2 (0.1) 2.2 (0.2) 2.4 (0.1) mg/dL) 4 h Dose 2 2.2 (0.1) 2.3 (0.2)2.5 (0.1) HCO₃ PreDose 1 27.3 (1.6) 27.6 (2.4) 28.0 (0.0) (23-33 4 hDose 1 26.7 (1.3) 27.6 (2.5) 28.5 (0.5) mmol/L) 4 h Dose 2 26.0 (1.5)28.0 (1.0) 28.0 (2.5) Anion Gap PreDose 1 20.2 (2.2) 21.6 (2.8) 22.7(0.7) (3-11 4 h Dose 1 20.7 (2.0) 22.2 (3.5) 21.4 (1.3) mEq/L) 4 h Dose2 21.5 (1.9) 21.5 (0.9) 20.5 (2.9)

A tablet formulation is considered to be a more convenient dose formthat will encourage patient compliance than ingestion of salty tastingliquids. Tablet formulas were evaluated for performance with respect tothe bowel cleansing surrogate markers of stool output volume and percentsolids in diarrheal stools. The stools were also evaluated to determinethe ability of the formulation to provide neutral movement ofelectrolytes between the body and the formulation. The goal of theproject was to attain stool output and clarity as close to the FDAapproved commercial products as possible while maintaining minimalmovement of electrolytes.

All of the formulas tested used a total of 24 tablets administered intwo 12 tablet doses. None of the formulations adversely affected serumelectrolytes. Most were able to produce stool volumes and percent solidssimilar to that achieved by the FDA approved commercial products.Although the stool volumes produced by the tablet formulations wereslightly lower than the commercial preparations, the equivalence orsuperiority of the stool percent solids measurements (a measure of coloncleansing) indicates that the commercial preparations may produceunnecessary output.

Formulas 8, 10, and 12 reduced the sodium content (by reducing sodiumsulfate) and provided compensating sulfate by adding magnesium sulfate,which also provided necessary magnesium to the formulation. Formulas 8,10, and 12 used potassium chloride as a source of those electrolytes andare very similar.

Formulas 8, 10, and 12 provide acceptable stool output, percent solidsmeasurements and minimal absorption/secretion of electrolytes. All showno propensity to significantly alter blood electrolytes and improveanion gap over SUPREP. All of these formulas are eligible for furtherstudy in colonoscopy patients.

1.-20. (canceled)
 21. A solid oral formulation for cleansing a colon ofa subject; the formulation comprising about 35.5 grams of sodiumsulfate, about 5.4 grams of magnesium sulfate, and about 4.5 grams ofpotassium chloride.
 22. The solid oral dosage form of claim 21 furthercomprising polyethylene glycol.
 23. The solid oral dosage form of claim21 further comprising one or more water-soluble excipients.
 24. Thesolid oral dosage form of claim 23, wherein the one or morewater-soluble excipients comprises sodium caprylate.
 25. The solid oraldosage form of claim 21, wherein the polyethylene glycol is PEG-8000.26. The solid oral dosage form of claim 32 is divided into a first doseand a second dose.
 27. The solid oral dosage form of claim 21, whereinthe solid oral dosage form is a tablet.
 28. The solid oral dosage formof claim 27, wherein the solid oral dosage form comprises administering24 to 28 tablets.